Approach

Febrile neutropenia is the most common life-threatening complication of cancer therapy.[1] ​If not treated in the first 48 hours, mortality approaches 50%.[87] It is therefore an oncological emergency.

Prompt administration of appropriate empirical antibiotics is associated with marked decrease in mortality.[17] Delaying administration of empirical antibiotics may lead to worse outcomes (e.g., serious medical complication, increased admission to intensive care unit, sepsis).[88]

A microbiological diagnosis is not made in the majority of patients with febrile neutropenia.[20][26]​ The likely organism can, however, be suspected based on:[4]

  • Site of infection

  • Underlying malignancy and associated immunological impairment

  • Type of chemotherapy

  • Severity and duration of neutropenia

  • Presence of mucositis

  • Predominant pathogens at the healthcare facility in which the patient is being treated

It is critical that patients are managed according to local healthcare institution algorithms and guidelines that have been developed based on knowledge of local and regional antibiotic susceptibility patterns [antibiograms]).

Patient-specific management should be informed by individual patient factors, including any prior history of antibiotic-resistant infection and allergy history.

Initial management

Most guidelines recommend administration of the first dose of empirical antibiotics as soon as possible (within 60 minutes of presentation) for a patient with neutropenia with fever (regardless of risk status and intended site of care, inpatient or outpatient).[3][20][44]​​​ Obtain blood cultures before administration of empirical antibiotics to increase likelihood of pathogen detection. These measures enable an initial evaluation (history, physical examination, laboratory investigations) and risk assessment to be performed without undue delay in therapy.

Risk assessment

Several validated risk assessment tools (e.g., Talcott system; Multinational Association of Supportive Care in Cancer [MASCC] score; and Clinical Index of Stable Febrile Neutropenia [CISNE] score) are available to help risk-stratify patients presenting with febrile neutropenia. See Criteria section.

While these tools may help to inform decisions regarding the optimal venue of care for a particular patient (i.e., inpatient or outpatient), they are not surrogates for clinical decision-making.

Patients are typically managed based on whether they are at high risk or low risk for complications or death.

High-risk patients include those who have any of the following:[4][75]​​

  • Talcott system group I to III; MASCC risk score <21; or CISNE ≥3

  • Inpatient status at the time of fever onset

  • Significant medical comorbidities or clinically unstable

  • Allogeneic haematopoietic cell transplantation

  • Anticipated prolonged severe neutropenia (absolute neutrophil count [ANC] ≤100 cells/microlitre and duration ≥7 days)

  • Hepatic or renal insufficiency

  • Uncontrolled or progressive cancer

  • Pneumonia or other complex infection

  • Use of certain immune and/or targeted treatments (e.g., phosphoinositide 3-kinase [PI3K] inhibitors)

  • Severe mucositis (grade 3 to 4).

Low-risk patients include those with no high-risk factors and most of the following:[4][75]​​[89]

  • Talcott system group IV; MASCC score ≥21; or CISNE score 0*

  • Outpatient status at the time of fever onset

  • No associated acute comorbid illness, independently indicating inpatient treatment or close observation

  • Anticipated short duration of severe neutropenia (ANC ≤100 cells/microlitre for <7 days)

  • Good performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-1)

  • No hepatic or renal insufficiency

*National Comprehensive Cancer Network guidelines consider CISNE <3 to be low risk at the initial risk assessment of patients with febrile neutropenia.

Inpatient versus outpatient treatment

Patients with febrile neutropenia who are assessed as high risk should be hospitalised and undergo inpatient treatment.[4][75]​​

Patients who are assessed as low risk can be considered for outpatient management.[4][75]​​​ Patients require a thorough evaluation and close observation for ≥4 hours before being considered for outpatient management.[75] Low-risk patients who may be suitable for outpatient management include those with:[4][75]​​​

  • stable vital signs,

  • non-critical laboratory results,

  • appropriate social care and home therapy arrangements (including access to a telephone and emergency facilities, and residing within 1 hour of a medical centre), and

  • ability to comply with and tolerate oral antibiotic therapy.

Several meta-analyses have found outpatient treatment to be a safe and effective alternative to inpatient management for low-risk patients, with no difference in treatment failure and death rates.[90][91][92]​ However, in one meta-analysis, ANC <100 cells/microlitre was identified as a potential predictor of outpatient treatment failure.[91]

Empirical antibiotics for high-risk patients

High-risk patients should be treated with empirical broad-spectrum antibiotics and hospitalised for further management.​[4][75]

The choice of antibiotic regimen should be based on coverage of the most likely pathogens and local susceptibility patterns (as per local healthcare institution algorithms and guidelines), as well as patient-specific factors (e.g., prior history of antibiotic-resistant infection and allergy history).

Antibiotic monotherapy

Empirical antibiotic monotherapy with a beta-lactam (e.g., cefepime, piperacillin/tazobactam, imipenem/cilastatin, or meropenem) is typically recommended for hospitalised patients with febrile neutropenia.[4][20][75]​​​ One Cochrane review reported lower risk of mortality, adverse events, and fungal superinfections in patients with febrile neutropenia treated with beta-lactam monotherapy compared with beta-lactam plus an aminoglycoside.[93]

In situations where anaerobic bacteria are likely to play a role, it would be appropriate to use piperacillin/tazobactam monotherapy as a first-line option, or combine metronidazole with cefepime, or use a carbapenem (meropenem or imipenem/cilastatin).[3]

Piperacillin/tazobactam monotherapy is a reasonable option in settings where resistance (e.g., extended-spectrum beta-lactamase [ESBL]-producing organisms) is not prevalent, based on local institutional bacterial susceptibilities.[4] Piperacillin/tazobactam has been shown to be non-inferior to cefepime and ceftazidime in randomised clinical trials.[94][95][96] Extended infusion of piperacillin/tazobactam has been found to be associated with superior treatment outcomes compared with bolus infusion in high-risk patients.[97]

Imipenem/cilastatin or meropenem may be preferred if ESBL-producing organisms are prevalent (based on local institutional bacterial susceptibilities).[4][98]

Antibiotic combination therapy

Combining a beta-lactam antibiotic with an aminoglycoside (e.g., tobramycin) could be considered (although not routinely recommended) if antibiotic resistance is suspected, with early discontinuation of the aminoglycoside if cultures do not reveal evidence of a drug-resistant organism.[4][75]​​

Combining a beta-lactam antibiotic with an aminoglycoside (either tobramycin or amikacin, but not gentamicin) may be preferable in patients with Pseudomonas aeruginosa sepsis, while awaiting susceptibility data, given the often multidrug resistance nature of this organism.[20][99]

At institutions with a high prevalence of multidrug-resistant gram-negative bacilli, combining piperacillin/tazobactam with tigecycline may be an option.[96] One randomised trial found this combination to be safe, well tolerated, and more effective (as measured by resolution of fever without alterations in antibiotics) than piperacillin/tazobactam monotherapy in patients with febrile neutropenia with high-risk haematological malignancies.[96] Mortality was similar for combination therapy and monotherapy.​

Indications for empirical extended-spectrum gram-positive coverage

Use of empirical vancomycin (or other extended gram-positive agents, e.g., linezolid, tedizolid, or daptomycin) is not routinely recommended for patients with febrile neutropenia, but may be considered in specific situations where risk of serious gram-positive infection (e.g., MRSA) is high, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or haemodynamic instability.[3][4][20][75]​​[100]​​ 

The presence of a central venous catheter alone in a patient with febrile neutropenia is not an indication for empirical vancomycin. The addition of vancomycin to first-line empirical monotherapy in a persistently febrile patient is not advised.[100][101]​​

Judicious use of vancomycin is warranted due to the increasing prevalence of antibiotic-resistant gram-positive organisms (e.g., vancomycin-resistant enterococci) and the potential for nephrotoxicity associated with this agent.[102][103]

Linezolid, tedizolid, or daptomycin can be used as an alternative in patients who are intolerant of vancomycin, and should be considered for patients with sepsis and known colonisation or prior infection with vancomycin-resistant enterococci.[104] Daptomycin should not be used in patients with pneumonia as it is inactivated by pulmonary surfactant.

Use of empirical vancomycin (or other gram-positive antibiotics) should be reassessed following 2-3 days of treatment, and discontinued if a gram-positive pathogen is not identified on blood cultures.[4]

Empirical antibiotics for low-risk patients

Low-risk patients who are suitable for outpatient management can receive oral therapy with a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) plus amoxicillin/clavulanate (or clindamycin if the patient is allergic to penicillin) if fluoroquinolone prophylaxis was not used before fever onset, and provided the patient does not have a history of infection or colonisation with a fluoroquinolone-resistant organism.[75][105]​ Fluoroquinolone monotherapy can also be considered in these patients.[106][107]​ 

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[68]

  • Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability).

  • Consult your local guidelines and drug information source for more information on suitability, contraindications, and precautions.

Some low-risk patients may be treated with an outpatient parenteral regimen, although there are no clinical trials to support their use.

Hospital admission and inpatient management should be considered if any of the following occur in low-risk patients undergoing outpatient management:[75]

  • No defervescence after 2-3 days of initial empirical antibiotic therapy

  • Fever recurrence after a period of defervescence

  • New signs or symptoms of infection

  • Use of oral therapy is no longer possible or tolerable

  • Change in the empirical regimen or an additional antimicrobial drug becomes necessary

  • Microbiological tests identify species not susceptible to the initial regimen

Treatment duration and de-escalation

Empirical antibiotic treatment (excluding extended-spectrum gram-positive coverage [see above]) is typically continued until neutrophil recovery (i.e., ANC ≥500 cells/microlitre and increasing).[3][4]

Once empirical antibiotics are started, the median time to clinical response is 5-7 days. Antibiotics should not be changed empirically in the face of persistent fever for the first 3-5 days, provided the patient is clinically stable.[108]

Negative blood cultures and source of infection unidentified

For clinically stable patients with persistent neutropenia who have defervesced (afebrile for at least 48 hours) on empirical broad-spectrum parenteral antibiotics and have negative blood cultures and no identified source of infection, consider:[4]

  • antibiotic de-escalation (e.g., to oral fluoroquinolone prophylaxis), or

  • discontinuation (if use of antibiotic prophylaxis is not standard protocol).

Evidence supporting safe early discontinuation of antibiotic therapy in patients with febrile neutropenia is growing, including in high-risk patients.[109][110][111][112][113][114][115]

Patients with persistent fever despite neutrophil recovery warrant continued empirical therapy and further diagnostic evaluation.[20]

Microbiologically documented infection

For patients with documented infection, the duration and de-escalation of antibiotic therapy should be individualised based on neutrophil recovery, speed of defervescence, specific pathogen and site of infection, and underlying disease.[4] Duration of treatment is typically 5-14 days for bacterial infections of the skin/soft tissue, sinuses, and lungs, and 7-14 days for most bacterial bloodstream infections.[4]

Catheter removal is recommended in the context of bloodstream infections with Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium jeikeium, Candida (or other yeasts), Acinetobacter, Stenotrophomonas maltophilia, Bacillus organisms, moulds, non-tuberculous mycobacteria, vancomycin-resistant enterococci (VRE), or other multidrug-resistant organisms.[4][20]​​​​​ ​

Catheters should also be removed in patients who have sepsis with a suspected line source; those with persistent bacteraemia despite effective antibiotic therapy; and those with tunnel or port pocket infection.[4][20]​​

Persistent fever

Patients with persistent fever beyond the first 3-5 days of empirical therapy require additional evaluation (e.g., imaging and microbiological testing) for a possible occult fungal infection, bacterial infection with cryptic foci or resistant organisms, or a viral infection.[3]​ If a thorough evaluation for infection is unrevealing in the face of persistent fever despite appropriate empirical therapy, a non-infectious cause for fever (e.g., drug fever, tumour fever, thromboembolism) should be considered.

Low-risk patients with persistent fever despite 2-3 days of empirical outpatient antibiotic therapy should be re-evaluated, with strong consideration for inpatient management.[75]

Empirical antifungal therapy

The addition of empirical mould-active antifungal therapy should be considered for high-risk patients with persistent fever despite ≥4 days of empirical antibiotic therapy.[3][4]

The choice and timing of empirical antifungal therapy is guided by local institutional guidelines, risk for invasive mould infection, prior mould-active antifungal prophylaxis (if received), severity of illness, and specific risk for drug-drug interactions or toxicity in an individual patient.

Colony-stimulating factors (CSFs)

The use of CSFs (i.e., granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) for treating patients with febrile neutropenia is controversial.

Limited data suggest a benefit with respect to time to neutrophil recovery, duration of antibiotic therapy, and length of hospitalisation, but no benefit with respect to overall mortality.[45][116] As such, the use of empirical CSFs (available as short-acting G-CSF formulations [e.g., filgrastim] or long-acting G-CSF formulations [e.g., pegfilgrastim, eflapegrastim, efbemalenograstim alfa, lipegfilgrastim], or as GM-CSF [e.g., sargramostim]) for treating patients with febrile neutropenia is typically not recommended.[57] 

Consideration may, however, be given to CSFs in high-risk patients with pneumonia, multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or uncontrolled primary disease; or in patients who are persistently febrile (>10 days), have profound neutropenia (ANC <100 cells/microlitre), are age >65 years, were hospitalised at the time of fever development, or who have had a previous episode of febrile neutropenia.[45][57]

In patients who have received prophylactic G-CSF, National Comprehensive Cancer Network guidelines recommend continuation of G-CSF, unless a long-acting G-CSF was used prophylactically.[45]

Use of this content is subject to our disclaimer